The field of the invention relates to methods for treating diseases and disorders associated with glucocorticoid receptor (GR) activity.
Glucocorticoid receptors (GR) are observed transcription factors that regulate gene expression. In non-activated cells, each receptor resides in the cytoplasm in a complex with chaperone proteins. Upon activation by a GR agonist, the GRs dissociate from the chaperones, form homo-dimers, and enter the nucleus where they interact with the regulatory sequences in gene promoters.
Glucocorticoid hormones are a mainstay of therapy of numerous hyperproliferative and inflammatory diseases including asthma, arthritis, psoriasis, dermatitis and others. They are also major component of chemotherapy of numerous blood cancers including acute childhood leukemia and multiple myeloma. However, some patients are initially resistant to glucocorticoids and most patients chronically treated with topical or systemic glucocorticoids develop resistance to these steroids (i.e., tachyphylaxis).
The biological effects of glucocorticoids are mediated by the glucocorticoid receptor (GR), a transcription factor that regulates gene expression via (i) DNA-dependent transactivation that requires GR dimerization and binding of GR dimer to gene promoters and (ii) DNA-independent transrepression mediated via negative interaction between the GR monomer and other transcription factors. While GR transrepression is the leading mechanism of anti-inflammatory and anti-proliferative effects of glucocorticoids, many metabolic side effects are mediated by GR transactivation. Thus, selective GR activators (called SEGRA) have been designed to prevent GR dimerization and to specifically shift GR activity towards GR transrepression. In preclinical studies SEGRA showed improved therapeutic index compared to glucocorticoids, hence holding a great potential for the treatment of patients.
The sensitivity to glucocorticoids directly depends on the amount of functional GR protein in cells. The 26S proteasome, a proteolytic complex that regulates the concentration of many cellular proteins, plays a central role in the regulation of GR protein stability. Proteasomes also are responsible for cell desensitization to glucocorticoids via accelerated hormone-induced GR degradation after treatment. This GR auto-down regulation is viewed as one of the important mechanisms for the development of acquired resistance to glucocorticoids in the clinic.